C-dialkylation of phenothiazine



United States Patent ice 3,393,193 C-DIALKYLATION 0F PHENOTHIAZINE JohnScotchi'ord Elliott, Eric Descamp Edwards, and Anthony David Brazier,London, England, assignors to Castro] Limited (formerly C. C. Wakefield& Company Limited), London, England No Drawing. Continuation-impart ofapplication Ser. No. 51,771, Aug. 25, 1960. This application May 1,1964, Ser. No. 364,300 Claims priority, application Great Britain, Aug.26, 1959, 29,236/59 2 Claims. (Cl. 260--243) This application is acontinuation-impart of our application No. 51,771 filed on Aug. 25,1960, now abandoned.

This invention relates to the C-dialkylation of phenothiazine.C-dialkylated phenothiazines, for example 3,7- dioctyl phenothiazinewhich is of commercial importance as a synthetic lubricant additive,have previously been made by the sulphurization of dialkylateddiphenylamines.

The preparation of mono-ethyl phenothiazine is described in Britishpatent specification No. 807,668. The process is carried out at aninitial pressure of from 20 to 1000 atmospheres and a temperature offrom 100 C. to 500 C. and there may be employed as a catalyst a mixtureof aluminum (in metal form or in combination with an aromatic amine)with a Friedel-Cratts cataylst which may be boron fluoride. No simplerway of alkylating phenothiazine was previously known, and no way at allof dialkylating phenothiazine.

Most Friedel-Crafts catalysts are quite ineffective for the alkylationof phenothiazine. Attempts to prepare dioctyl phenothiazine wereentirely ineffective when the following conventional Friedel-Craftscatalysts were used, no product being recovered in any case; stannicchloride, phosphoric acid, tetraphosphoric acid, concentrated sulphuricacid, aluminum chloride, titanium tetrachloride, and bismuthtrichloride. Similarly complexes of boron trifluoride with bases such aspyridine, ethylamine and diphenylamine will not catalyze the alkylationreaction, and anhydrous boron trifluoride or complexes thereof withacidic complexing agents such as phosphoric acid and acetic acid promotepolymerization of the alkene rather than alkylation of thephenothiazine.

It is an object of this invention to effect a one-step dialkylation ofphenothiazine.

It is another object of this invention to provide a cheaper and easierroute to alkylated phenothiazing than those hitherto known.

It is another object of this invention to provide a Friedel- Crafts-typecatalyst for the di-alkylation of phenolthiazine which is novel for thispurpose.

Other objects will appear from the specific examples of the inventiongiven below.

The invention provides a process for the C-dialkylation of phenothiazinewhich process consists essentially in the steps of heating together, ata temperature of from 50 C. to 150 C. in a fluid reaction medium,phenothiazine and an alkene having the formula where R is a saturatedmonovalent alkyl radical having from 1 to 9 carbon atoms, effectingalkylation of the phenothiazine by the alkene by the use, as a catalyst,of a boron trifluoride complex selected from the group consisting ofhydrates, alcoholates, etherates, complexes with carboxylic acid estersand complexes with nitriles, and recovering the dialkylatedphenothiazine.

The catalysts are boron trifluoride complexes, preferably with water,examples of which are BF .H O and BF 2H O. The complexes may also bewith alcohols,

3,393,193 Patented July 16, 1968 ethers, carboxylic acid esters, andnitriles. Examples of catalysts for use in this invention are:

Boron fluoride ethyl acetate complex BF .CH COOC H Boron fluoride methylbenzoate complex BF .C H COOCH Boron fluoride methanol complexes BF .CHOH,

BF .2CH OH Boron fluoride ethanol complex BF .C H OH Boron fluorideglycol complex BF .(CH OH) Boron fluoride etherate BF .(C H O Boronfluoride methyl amyl ether complex Boron fluoride anisole complex BF .CH OCH Boron fluoride tetrahydrofuran complex BF .C H O Boron fluoridedioxan complex BF .C H O Boron fluoride acetonitrile complex BF .CH CNBoron fluoride benzonitrile complex BF .C H CN Boron fluoride complexeswith o-mand p-toluonitrile.

Another satisfactory catalyst is 40% aqueous fluoboric acid, which isbelieved to function in the same way as the boron fluoride hydrates.

The invention only covers complexes of boron trifluoride with knownorganic compounds in the classes given above. However, obviously othercomplexes can be used in place of those listed. Thus for instance acomplex with any aliphatic alcohol having a saturated alkyl chaincontaining from 1 to 6 carbon atoms would clearly be equivalent for thepurpose in question to the specific examples of alcohol complexes givenabove. Similarly complexes with ethers having two saturated alkyl chainseach containing from 1 to 6 carbon atoms are clearly equivalents; alsoethers where one group is phenyl or naphthyl. Similarly complexes withcarboxylic acid esters having saturated alkyl radicals with from 1 to 6carbon atoms in the acid and alcohol groups are clearly equivalent; alsocarboxylic acid esters where one group is phenyl or naphthyl. Similarlycomplexes with nitriles of naphthyl and saturated alkyl radicals havingfrom 1 to 6 carbon atoms are clearly equivalent.

It was not foreseeable from the prior art that these particularcatalysts would be effective. Bruner has taught in United States Patent2,376,119 the use of boron trifluoride hydrates to alkylate aromaticcompounds e.g. benzene, with normally gaseous olefins under pressure.Similarly Schultz et al. taught in United States Patent No. 2,425,839the use of boron trifluoride alcoholates to alkylate aromatic compoundssuch as benzene. But it has never been suggested that heterocycliccompounds can necessarily be alkylated in the same way as aromaticcompounds. In Chemical Reviews it was stated (1954, pages 813-814), wellafter the issue of patents to Bruner and Schultz, that no alkylation ofphenothiazine by the FriedeL Crafts method had been reported, and thesubsequent British specification No. 807,668 taught the use of adifferent and more complex catalyst.

The alkylation of thiophene with boron trifluoride complex catalysts hasalso been reported. But thiophene is well known to be more amenable toalkylation than benzene, whereas phenothiazine is not only much lessreactive than benzene, but requires the use of complex catalysts foralkylation which do not de-activate the molecule by co-ordinating withthe nitrogen atom.

It is also noteworthy that:

(a) Other boron trifluoride complexes as hereinbefore mentioned do notcatalyze the reaction,

b) Such similar heterocyclic compounds as phenazine, pyridine,quinoline, benzimidazole and benzothiazole are not alkylated by thecatalysts of the invention,

3 (c) The presence in the alkylating agent of a methyl group adjacentthe double bond is essential.

The choice of alkylating agent is therefore critical. Examples ofsuitable alkenes are:

Isobutylene Di-isobutylene Tri-isobutylene Z-methyl-but- 1ene2-methyl-pent-1-ene Z-methyl-heptl-ene Z-methyl-nonl-ene2-methyl-undec-1-ene Di-isobutylene is preferred as better yields havebeen obtained with it than with other alkenes. In certain cases, it ispossible to employ in the reaction mixture the corresponding tertiaryalcohol and form the alkene in situ in the reaction mixture. Thetertiary alcohol is thus first decomposed by the boron fluoride complexto provide the alkene which then reacts with the phenothiazine.

The presence of the methyl group adjacent to the double bond of thealkene has been found to be essential; atempts to alkylate phenothiazinewith compounds such as decene-l, propylene tetramer and 2-ethyl hexene-lhave proved unsuccessful.

Although the reaction will proceed in the absence of a solvent, anon-polar hydrocarbon solvent is preferably employed, e.g., heptane,iso-octane, or petroleum ether (B.P. 80100 C. or 100-120 C.). Thepresence of some aromatic hydrocarbons does not appear to bedetrimental, although theoretically these might be alkylated too, and,if this occurred, it would reduce the yields.

The recation is preferably carried out at atmospheric pressure, althoughsuperatmospheric pressure may be used. A reaction temperature of between80 and 120 C. has been found preferable in carrying out the invention.The reaction can be promoted and yields improved by the use of acatalyst promoter, e.g., an organic sulphonic acid, such asp-toluenesulphonic acid, used in amounts of 1 to 10%, preferably 5% byweight on the weight of phenothiazine present.

The products of the invention are invariably dialkylated, and it maytherefore be convenient to use appropriate molar quantities of alkeneand phenothiazine, or possibly a small excess of alkene. However,reaction proceeds with any proportions of reagents, and the invention isnot limited to any particular proportions. Similarly, reaction proceedswhen catalyst is present irrespective of the amount of catalyst, but itis preferred to use from 0.1 to 3 moles, e.g., 0.2 to 1.5 moles, ofcatalyst per mole of phenothiazine to obtain optimum yields. 7

The following specific examples illustrate the process.

EXAMPLE I Preparation of 3,7 dioctyl phenothiazine The apparatusconsisted of a S-necked 1 litre flask fitted with a thermometer pocket,mercury sealed stirrer, and a reflux condenser.

Into the flask were placed:

Phenothiazine (0.5 mol) gm 100 Diisobutylene (1.0 mol) gm 112 BF -2H O(0.1 mol) (catalyst) gm 10.4 p-Toluenesulphonic acid (catalyst promoter)gm 5 Heptane mls 200 4 v the product. This was repeated twice more, thesolution being heated each time. The heptane layer was then separatedand the solvent removed by distillation. The remaining solid wasrecrystallised from heptane.

By these means 126 grams of a pale green crystalline material melting at1635 C. were obtained, this representing a 60% yield. After one furtherrecrystallisation from heptane the M.P. was raised to 167 C.

EXAMPLE II Preparation of 3,7 dioctyl phenothiazine The process ofExample I was repeated though with 200 mls. isooctane as solvent, butthe catalyst promoter was omitted. 114 gm. product were isolated withdifliculty.

The yield in this case was 53%.

EXAMPLE III Preparation of 3,7 dioctyl phenothiazine The same amounts ofreactants were used as in Example I (including catalyst promoter) butthe reaction was performed in petroleum ether (B.P. -100 C. andcontaining about 11% aromatics).

The solution was refluxed gently for 4 hours. The bulk temperatureremained at 9193 C. throughout.

Finally 141 gms. of the product were isolated representing a yield of67%, after one recrystallisation from heptane.

EXAMPLE IV Preparation of 3,7-didodecyl phenothiazine This substance wasprepared by the procedure described in Example I from Phenothiazine (0.1mol) gm 19.9 Triisobutylene (0.2 mol) gm 33.6 BF 2H O (0.15 mol) gm 15.6p-Toluenesulphonic acid gm 0.5 Pet. ether (80-100 C. boiling range) ml50 The reaction product was very resinous, but, after recrystallisationfrom heptane, there were obtained 7.5 gms. (14%) of didodecylphenothiazine, melting at 141 C.

Analysis indicated the compound to contain 5.27% S, the theoreticalfigure for didodecyl phenothiazine being 5.98% S.

EXAMPLE V Preparation of 3,7-di-t-butyl phenothiazine from t-butylalcohol Into a flask fitted as described in Example I were placed thefollowing:

Phenothiazine (0.2 mol) grn 39.8 t-Butyl alcohol (0.4 mol) gm 29.6 BF 2HO (0.4 mol) gm 41.6 p-Toluenesulponhic acid gm 2.0 Pet. ether (BO- C.boiling range) ml 200 The mixture was refluxed for five hours withstirring, after which it was poured into hot 10% caustic soda solutionand shaken. It was then extracted with petroleum ether, the organiclayer being separated, washed with water, and the solvent removed bydistillation.

The grey solid so obtained was recrystallised from heptane and then fromalcohol, yielding 16 grams (23%) of a solid melting at 206 C.

This solid was further purified by dissolving in petroleum ether andshaking first with dilute aqueous hydrochloric acid, then with diluteaqueous caustic soda and finally with water. The solution was then driedover anhydrous magnesium sulphate and the solvent removed bydistillation.

The di-t-butyl phenothiazine so obtained melted at 210 C. and contained4.46% N and 9.77% S, the theoretical figures being 4.50% N and 10.29%S.-

5 EXAMPLE v1 Preparation of 3,7 dioctyl phenothiazine; use ofalternative catalysts A series of preparations of 3,7 dioctylphenothiazine were carried out by the general procedure set forth inExample I, but substituting various catalysts for boron fluoridedihydrate. The results of these experiments are summarised in Table I.

TABLE I Moles of Moles oi Percentage Melting Catalyst Pheno- Catalystyield of point thiazine product C.)

BFa-ZCHsOH 0.1 0.05 35 167. 5

6 is carried out in the presence of l10% by weight based on the weightof the phenothiazine of p-toluene sulfonic acid co-catalyst.

References Cited UNITED STATES PATENTS 2,376,119 5/1945 Bruner et a1260671 2,425,839 7/1947 Schulze et al. 260671 2,469,823 5/1949 Hansfordet a1 260329 2,721,886 10/1955 Pines et al. 260-315 2,859,251 11/1958Linn 260-624 FOREIGN PATENTS 807,668 1/ 1959 Great Britain.

OTHER REFERENCES Caesar, J. Am. Chem. Soc., vol. 70, p. 36233625 Pineset al., J. Am. Chem. Soc., vol. 72, p. 1568-1571 JOHN D. RANDOLPH,Primary Examiner.

WALTER A. MQDANCE, N. S. MILESTONE,

Examiners.

H. I. MOATZ, Assistant Examiner.

1. A PROCESS FOR THE PREPARATION OF 3,7-DIOCTYL PHENOTHIAZINE COMPRISINGTHE STEPS OF REFLUXING PHENOTHIAZINE AND DI-ISOBUTYLENE IN NON-POLARHYDROCARBON SOLVENT HAVING A BOILING POINT ABOUT 80-120*C. IN THEPRESENCE OF 0.2 TO 1.5 MOLS PER MOL OF PHENOTHIAZINE OF A CATALYSTCONSISTING ESSEENTIALLY OF BORON-TRIFLUORIDE-DIHYDRATE.